PROJECT SUMMARY The proposed research focuses on the development of novel therapeutic agents for the treatment of malaria caused by P. falciparum. Preliminary studies have discovered some novel natural products and derivative molecules with potent in vitro activity against both sensitive and multidrug resistant malaria strains including the newly emerging artemisinin resistant parasite line. New compounds are low in toxicity and possess good therapeutic indice. This SBIR Phase I project aims to obtain proof of concept in vivo efficacy and toxicity data. Studies include: (I) Scale up isolation and purification of natural products and synthesis of derivative compounds; (II) In vivo efficacy studies in an immunocompromised P. falciparum BXN mice model or P. berghei mice model; (III) In vivo evaluation for acute and sub-acute toxicity, developmental toxicity, and neurotoxicity. The novelty of the project is the discovery of new molecular entities. The project involves standard approaches to drug development, but the multidisciplinary team and inter-institution collaboration that has been assembled will accelerate the generation of preclinical candidates.